There is considerable evidence available in the literature supporting
the idea that brain monoamine systems play a key role in
the pathogenesis of affective disorders, in particular depression.
These hypotheses have primarily taken the form of proposing
abnormal regulation in serotonin (5-HT) (Coppen, 1967) and the
catecholamines norepinephrine (NE) (Bunney and Davis, 1965;
Schatzberg and Schildkraut, 1995) and dopamine (DA) (Kapur and
Mann, 1992)in depression. Early studies have focused largely on
levels of monoamines and their receptors and have stimulated several theories about the pathophysiology of depression, including the
monoamine deficiency and receptor sensitivity hypotheses. However, we have to acknowledge today that these hypotheses have
not provided us with an ultimate explanation about the role of
monoamines in depression. Nor can the pathophysiology of depression be explained simply by dysregulation of 5-HT and/or NE
or DA transmission. Recent advances in molecular and cellular
neurobiology have offered new insights into mechanisms possibly involved in the pathophysiology of depression, and also into
the mechanisms of action of antidepressant treatment modalities
(for reviews see Duman et al., 1997; Manji et al., 2001; Sulser,
1989). These studies have shown that chronic antidepressant treatment regulates intracellular signal transduction pathways and the
expression of specific target genes.

The purpose of this chapter is to provide a concise review
of clinical studies on the role of 5-HT and NE transmission
in depression. However, several caveats need to be considered.
First, depression is not a homogeneous disorder, and classifying
a given patient with depression is a clinical decision and remains a
subjective interpretation of a syndrome, even though the decision
should be based on established diagnostic criteria such as DSMIV criteria (American Psychiatric Association, 1994). However,
identifying homogeneous groups of patients with depression has
proven to be a virtually impossible task. This might explain some
of the variability of biological findings in depression and the
lack of consistent replication of many intriguing findings. Second,
almost all patients being studied in clinical studies have been
exposed to different pharmacological and non-pharmacological
treatments before entering studies. This may confound the results of
clinical and preclinical studies. Finally, there is no methodological
homogeneity in processing experimental samples and assays. It is
remarkable that despite these methodological problems a number of
neurochemical findings have been replicated in the past in patients
with depression and have provided researchers with insight into the
underlying biology of this devastating illness.

SEROTONIN

Serotoninergic neurons are located in the brainstem where they
can project to virtually every part of the central nervous system,
often modulating neuronal responses to other neurotransmitters. As
a result of this widespread projection pattern, 5-HT is known to be
involved in the regulation of a wide variety of functions, including
mood, anxiety, aggression, sleep, arousal, appetite and sexual function. However, it has to be acknowledged that the precise details
of the mechanisms involved are not fully understood. Interest into
the potential role of 5-HT in the pathophysiology of psychiatric
disorders was spurred by the observation that hallucinogens such
as lysergic acid diethylamide and psilocybin inhibit the peripheral
actions of 5-HT. This led to the hypothesis that brain serotonergic function might be altered in patients with psychiatric disorders
(Gaddum and Hameed, 1954; Wooley and Shaw, 1954). Further
evidence for the importance of serotonergic mechanisms in depression was inferred by the observation that imipramine improved
mood and boosted psychomotor activity (Kuhn, 1958). This initial observation of the antidepressant properties of imipramine led
to more intensive testing in clinical trials of this compound and
later the other tricyclic antidepressants and monoamine oxidase
inhibitors for the treatment of depression. The results from these
clinical trials, indicating that the action of antidepressant drugs
involves enhancement of brain serotonergic activity, and further
evidence for dysfunction at multiple levels in the serotonergic system of depressed patients culminated in the 'serotonin hypothesis'
of depression (Maes and Meltzer, 1995). Whether this serotonergic dysfunction is the primary cause of depression or is a necessary risk factor remains unclear and is the subject of intensive
research.

Seasonality of Serotonergic Function

One factor that has to be considered when evaluating the potential role of 5-HT in depression is the seasonal variation in central
and peripheral 5-HT function in humans. There is considerable
evidence in the literature suggesting a seasonal variation in several phenomena, such as mood, feeding behaviour and suicide, and
that these phenomena may be related to changes in central and
peripheral 5-HT function (Maes et al., 1995). In healthy subjects
and non-psychiatric patients several studies have described seasonal variations in central and peripheral 5-HT function. Studies of
humans distinguish whether measures are static (e.g. biochemical
levels in body fluids or blood elements) or dynamic (e.g. neuroendocrine responses to pharmacologic challenges).

Several lines of evidence based on static measures support the
hypothesis of seasonal fluctuations of 5-HT function in humans:
(1) hypothalamic 5-HT concentrations in human post-mortem brain
specimens are decreased in winter after values peak in autumn
(Carlsson et al., 1980), (2) levels of plasma tryptophan, the precursor of 5-HT, show a bimodal seasonal pattern (Maes et al.,
1995), (3) platelet 5-HT uptake and 3[H]-imipramine binding show
a seasonal pattern, albeit with some differences in seasonal peaks
and troughs (Arora and Meltzer, 1988; DeMet et al., 1989; Tang

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